There are a large number of patents and patent applications disclosing different substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles. This class of compounds has properties making the compounds useful as inhibitors of gastric acid secretion. For example the compound, (5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl!sulphinyl!-1H-be nzimidazole) with the generic name omeprazole, described in i.e. EP 5129, is useful as an antiulcer agent. Other compounds of interest are for instance the compounds with the generic names lansoprazole, pantoprazole, pariprazole and leminoprazole.
These compounds as well as structurally related sulphoxides, have a stereogenic centre at the sulphur atom and thus exist as two optical isomers, i.e. enantiomers. If there is another stereogenic centre in the molecule, these compounds can exist as pairs of enantiomers. Corresponding sulphides of such compounds which already contain a stereogenic centre are not pro-chiral compounds, but chiral compounds. However, the sulphur atom in these compounds does not have asymmetry and therefore they are referred to as pro-chiral sulphides in respect of this invention.
Even though this class of chiral sulphoxides has been discussed in the scientific literature since the late seventies, there is not yet any efficient asymmetric process described for the synthesis of the single enantiomers thereof. The single enantiomers of pharmacologically active compounds have met an increased interest in the last years because of improved pharmacokinetic and biological properties. Therefore, there is a demand and need for an enantioselective process that can be used in large scale for the manufacture of the single enantiomers of pharmacologically active compounds, such as for instance optically pure, substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles.
There are processes for resolution of different substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles disclosed in the prior art. Such resolution processes are for example described in DE 4035455 and WO 94/27988. These processes involve synthetic steps wherein a diastereomeric mixture is synthesised from the racemate of the corresponding substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles. The diastereomers are then separated and finally one of the separated diastereomer is converted to the optically pure sulphoxide in a hydrolytic step.
These resolution methods involving diastereomeric intermediates, suffer from at least three fundamental disadvantages namely:
1) The substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazole, as a racemic intermediate, has to be further processed in a couple of reaction steps before the single enantiomers can be obtained. PA1 2) The resolution processes described involve complicated separation steps. PA1 3) There is a large waste of highly refined material when the unwanted stereoisomer, in the form of the opposite diastereomer, is separated and discarded. PA1 1) Methylation of the mercapto group. PA1 2) Attaching a protective group to one of the nitrogen atoms in the imidazole moiety. PA1 3) Asymmetric oxidation of the sulphide to a sulphoxide. PA1 4) Reacting the obtained methyl sulphoxide derivative with a strong base, such as lithium diisopropyl amide (LDA), in order to abstract a proton from the methyl group. PA1 5) Alkylating the lithium salt of the methyl sulphoxide derivative with 4-chloro-1-iodobutane giving a 5-chloropentyl sulphoxide derivative. PA1 6) Attaching the pyrazolyl group to the n-pentyl chain. PA1 7) Removing the protective group.
Further, prior art describes for instance enantioselective synthesis of the single enantiomers of a sulphoxide agent Ro 18-5364, (5,7-dihydro-2-(4-methoxy-3-methyl-2-pyridinyl)methyl!-sulphinyl!-5,5,7, 7-tetramethylindeno-5,6-d!-imidazol-6-(1H)-one), See Euro. J. Biochem. 166 (1987) 453. The described process is based on an enantioselective oxidation of the corresponding prochiral sulphide to said sulphoxide. The experimental conditions used during the oxidation are stated to be in accordance with the asymmetric sulphide oxidation process developed by Kagan and co-workers (Pitchen, P.; Deshmukh, M.; Dunach, E.; Kagan, H. B. J. Am. Chem. Soc. 106 (1984), 8188). The authors report that the obtained crude product of the sulphoxide, showing an enantiomeric excess (e.e.) of about 30%, can be purified to an essentially optical pure sulphoxide (e.e.)&gt;95%! by several steps of crystallisation. However, the yields and the number of crystallisation steps are not reported.
It is of interest to note that attempts of the Applicant to repeat the experimental conditions described and reported above, in the preparation of the single enantiomers of Ro 18-5364 afforded crude sulphoxide with an enantiomeric excess of only 16%.
In order to obtain the optically pure 2-(2-pyridinylmethyl-sulphinyl)-1H-benzimidazoles of interest, e.g. one of the single enantiomers of omeprazole, the Applicant obtained crude sulphoxides with a typical enantiomeric excess of about 5% or even lower with the above described method; See Reference Example A, below.
In the above mentioned process for asymmetric oxidations of sulphides to sulphoxides developed by Kagan and co-workers (J. Am. Chem. Soc. (1984) cited above), the oxidation is performed by using tert.butyl hydroperoxide as oxidising agent in the presence of one equivalent of a chiral complex obtained from Ti(OiPr).sub.4 /(+)-or (-)-diethyl tartrate/water in the molar ratio of 1:2:1.
Kagan and co-workers reported that sulphoxide products with the highest enantioselectivity could be obtained when sulphides bearing two substituents of very different size were subjected to an asymmetric oxidation. For instance, when aryl methyl sulphides were subjected to oxidation, it was possible to obtain the aryl methyl sulphoxides in an enantiomeric excess (e.e.) of more than 90%.
However, when the substituents attached to the sulphur atom of the pro-chiral sulphide have a more equal size, a moderate or poor enantioselectivity was obtained. For instance, when benzyl p-tolyl sulphide is subject to oxidation under the conditions proposed by Kagan and co-workers, the e.e. observed is only 7%.
There have been attempts to improve the conditions for asymmetric oxidation of sulphides. For example, Kagan and co-workers (Zhao, S.; Samuel, O.; Kagan, H. B. Tetrahedron (1987), 43, 5135) found that a higher enantioselectivity generally could be obtained if the tert-butyl hydroperoxide in the system discussed above was replaced by cumene hydroperoxide in the oxidation of the sulphide. For instance an enantiomeric excess of 96% could be obtained in the asymmetric oxidation of methyl p-tolyl sulphide.
Thus, as a proposed method for asymmetric oxidation of sulphides, Kagan used cumene hydroperoxide with the system Ti(O-iPr).sub.4 /diethyl tartrate/water (1:2:1) in methylene chloride at -23.degree. C. The authors reported a decreased enantioselectivity when the amount of titanium reagent was lower than 0.5 equivalent. (See Tetrahedron (1987) cited above.)
Using this improved asymmetric oxidation process with one equivalent titanium reagent in order to obtain the optically pure 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles, e.g. one of the single enantiomers of omeprazole, the Applicant obtained a typical enantiomeric excess of about 10%; See Reference Example B, below.
The reaction conditions and their relevance in respect to the enantiomeric excess obtained for chiral sulphoxides in general, have also been discussed by Kagan and co-workers, See Synlett (1990), 643. For example a temperature of -20.degree. C. was found to be required for a high enantioselectivity and in some cases as low as -40.degree. C. was used by Kagan and co-workers to obtain the highest enantioselectivity. Further, the authors state that the enantioselectivity will be decreased when changing the organic solvent used in the oxidation from methylene chloride to for instance toluene. Methylene chloride and 1,2-dichloroethane are discussed as preferred solvents for the oxidation. It is to be noted that neither the low temperatures nor the proposed solvents are satisfactory from an industrial point of view.
Recently, a large scale asymmetric synthesis of an acylcholesterol acyltransferase (ACAT) inhibitor has been developed by Pitchen and co-workers (Pitchen, P; France, C. J.; McFarlane, I. M.; Newton, C. G.; Thompson, D. M. Tetrahedron Letters (1994), 35, 485). The discussed ACAT inhibitor, general named "compound RP 73163", is a chiral sulphoxide bearing one 4,5-diphenyl-2-imidazolyl group and one 5-(3,5-dimethyl-1-pyrazolyl)-1-pentyl group on the stereogenic center, i.e. the sulphur atom. However, the compound, which is not a substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazole type compound according to the present invention, has two large substituent groups attached to the stereogenic centre just as the compounds obtained in the present invention.
Initially, the corresponding prochiral sulphide of RP 73163, bearing these two large substituents on the sulphur atom, was oxidised using the above mentioned asymmetric oxidation method proposed by Kagan (See Tetrahedron (1987) cited above). The prepared sulphoxide is reported to be obtained in a good chemical yield but the enantiomeric excess of the sulphoxide was 0% (racemic mixture). However, these discouraging results are not surprising for a chemist since in the literature the highest enantioselectivities for the titanium tartrate mediated reactions always have been reported in the case of oxidation of rigid (e.g. cyclic) sulphides or sulphides bearing two substituents of very different size. The authors conclude that the enantioselectivity for this type of oxidations is mainly governed by steric effects.
With respect of the information disclosed in published literature and in order to have a suitable prochiral substrate for an asymmetric oxidation, Pitchen and co-workers (See Tetrahedron Letters (1994) cited above) have decided to reduce the size of one of the substituents attached on the sulphur atom in the sulphide. An intermediate of choice for such a process may be a N-protected 4,5-diphenyl-2-imidazolyl methyl sulphide which after oxidation is obtained as the corresponding sulphoxide. The enantiomeric excess of the formed sulphoxides is in the range of 98-99%. However, the synthetic route becomes more complicated using an intermediate than the originally method proposed for the asymmetric oxidition of 2-5-(3,5-dimethylpyrazol-1-yl)pentylthio!-4,5-diphenyl imidazole. Starting from 4,5-diphenyl-2-imidazolethiol, the synthetic route has to include the following synthetic steps:
It is obvious that the proposed complicated approach by optimising the size of the substituents is not suitable for preparation, especially not in a large scale.
It should be noted that the process according to the present invention applied to the pro-chiral sulphide of RP 73163, surprisingly gives RP 73163 in an enantiomeric excess of &gt;85-90%, See Reference Examples E and F, below.
The prior art literature does not disclose nor propose a suitable enantioselective process which can be used in large scale for obtaining the single enantiomers of 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles. Therefore, there is still a long-felt demand for such an enantioselective process for the manufacture of substituted optically pure 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles as well as other structurally related suiphoxides.